PURPOSE: Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). METHODS: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. KEY FINDINGS: We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. SIGNIFICANCE: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.
Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy / R.S. Møller, Y.G. Weber, L.L. Klitten, H. Trucks, H. Muhle, W.S. Kunz, H.C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I.-M. Rückert, H.-E. Wichmann, J.P. Ernst, C. Schurmann, H.J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, F. Zimprich, M. Mörzinger, M. Feucht, A. Suls, S. Weckhuysen, L. Claes, L. Deprez, K. Smets, T. Van Dyck, T. Deconinck, P. De Jonghe, R. Velizarova, P. Dimova, M. Radionova, I. Tournev, D. Kancheva, R. Kaneva, A. Jordanova, D.B. Kjelgaard, A.-E. Lehesjoki, A. Siren, S. Baulac, E. Leguern, S. Von Spiczak, P. Ostertag, M. Leber, C. Leu, M.R. Toliat, P. Nürnberg, A. Hempelmann, F. Rüschendorf, C.E. Elger, A.A. Kleefuß-Lie, R. Surges, V. Gaus, D. Janz, B. Schmitz, K.M. Klein, P.S. Reif, W.H. Oertel, H.M. Hamer, F. Rosenow, F. Becker, C. Marini, R. Guerrini, D. Mei, V. Norci, F. Zara, P. Striano, A. Robbiano, M. Pezzella, A. Bianchi, A. Gambardella, P. Tinuper, A. La Neve, G. Capovilla, P. Vigliano, G. Crichiutti, F. Vanadia, A. Vignoli, A. Coppola, S. Striano, M.T. Giallonardo, S. Franceschetti, V. Belcastro, P. Benna, G. Coppola, A. De Palo, E. Ferlazzo, M. Vecchi, V. Martinelli, F. Bisulli, F. Beccaria, E. Del Giudice, M. Mancardi, G. Stranci, A. Scabar, G. Gobbi, I. Giordano, B.P.C. Koeleman, C. De Kovel, D. Lindhout, G.-J. De Haan, U. Ozbeck, N. Bebek, B. Baykan, O. Ozdemir, S. Ugur, E. Kocasoy-Orhan, E. Yücesan, N. Cine, A. Gokyigit, C. Gurses, G. Gul, Z. Yapici, C. Ozkara, H. Caglayan, O. Yalcin, D. Yalcin, D. Turkdogan, G. Dizdarer, K. Agan. - In: EPILEPSIA. - ISSN 0013-9580. - 54:2(2013 Feb), pp. 256-264.
Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy
A. Vignoli;
2013
Abstract
PURPOSE: Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). METHODS: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. KEY FINDINGS: We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. SIGNIFICANCE: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.
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